Production of benzamidocyclohexane



Patented May 23, 1950 PaonUc'noN or? nsnzAMmocYcLo- Harry W. GrimmeLE isQQn, and Alfred Guentlier,

Riegelsville,

Pa., asslg'nors to General Aniline & Film Corporation, New York, N. Y.', a corporation' of Delaware No Drawing. Amillciticn June 28, 1945, Serial No. 602,154

1 Claim.- "(01. 260-558) This invention relates to a new method for I the production of organic amides.

There are several known methods for the preparation of organic amides which have been used with varying degrees of success. The most widely used of these prior known methods involves the reaction of carboxylic acid chlorides and amines. Other processes involve the reaction .phosphazo compounds with organic carboxylic acids in accordance with the following general equation:

2R1CONHR+HPO2 wherein R and R1 represent members of the group consisting of an aliphatic chain, an

alicyclic nucleus, an aromatic nucleus and a' .heterocycli'c nucleus and their substitution products. In the case of the aliphatic acids there should be no amino substituents in the molecule. It has also been discovered that the salts of the carboxylic acids are not suitable to this reaction. The amides which are produced by this condensation may be straight aliphatic, alicyclic,

aromatic or heterocyclic amides or they may consist of any desired combination of these groupings such as aliphatic-heterocyclic amides, ardmatic-alicyclic amides, aliphatic-aromatic amides and the like.

Where polycarboxylic acids are reacted with the phosphazo compounds, the monoamide, the,

diamide, or the imide may be formed depending upon the nature of the acid and the reaction conditions. Thus, in the case of dicarboxylic' acids,

where the two carboxylic acid groups are attached to the adjacent carbon atoms and on thesame side of the molecule as in cis-isomers the imide or monoamide is formed. Phthalic acid, for instance, invariably yields only N-phenyl- 'phthalimide even when reacted with an excess of phenylphosphazo-anilid'e (1 mol of phthal c acid to 2 mols of CeH5N=P-NHCcHs). Maleic acid. on the other hand, produces maleaniic acidwhen using the theoretical quantity of phospha'zo compound required for dianilide formation. The structural similarity of phthalic acid to maleic acid suggests that maleanil is the primary product of the reaction between maleic acid and phenylphosphazo anilide. Since maleanil is very readily hydrolized, the actual product isolated is maleanilic acid 'HCC-N t t H Where the two carboxylic acid groups are separated by at least one carbon atom, as in isophthalic acid or terephthalic acid, or where the two carboxylic acid groups are not situated on the same side of the molecule as in trans-isomers, such as fumaric acid, the conversion is exclusively to the dianilldes.

'The organic phosphazo compounds employed in this process may be obtained by the process of our copending application Serial No. 587,211, filed April 7, 1945, now abandoned, for Preparation of organic phosphazo compounds, which involves the reaction of an organic primary amine with phosphorus trichloride preferably in the ratio of 5 mols of the amine to 1 mol of the phosphorus trichloride in the presence of an organic solvent. This reaction may be graphically represented as follows:

in which n is 1 or 2 and R represents an aliphatic chain such as methyl, ethyl, propyl, butyl, amyl, octyl, dodecyl, stearyl, and the like, an alicyclic nucleus such as cyclopentyl, cyclohexyl and the like, an aromatic nucleus such as phenyl, naphthyl, and the like, or a, heterocyclic nucleus such as pyridyl, quinolyl, carbazolyl, diphenylene oxide and the like. These radicals representing R may also be substituted by such substituent groups as halogens, alkyl, alkoxy, amino, substituted amino, and sulfo groups. The R radical may not, however, be substituted by a carboxyl group; or by a nitro group which Willbe in 0- or p-position to the linkage of the R radical to the remainder of the molecule.

In carrying out our new process for theproduction of organic amides, 1 mol of the organic phosphazo compound is reacted with 1 mol of a dicarboxylic acid or 2 mols of a monocarboxylic acid in an organic solvent atroom temperature (20? C.) or higher and preferably at therflux. temperature of the solvent. In placeof the 1 mol of organic phosphazo compound, an equiv,

3 alent amount oi the reaction solution obtained by reaction of an organic amine and phosphorus trichloride by the method of our copending application serial No. 587,211 may be employed as recommended in our said copending application in cases where it is found, difllcult or unnecessary to effect the isolation of the phosphazo compound. In such cases, the molar equivalency of the reaction solution will be based upon the amount of active phosphorus compounds contained therein. when the condensation oi. the

phosphazo compound and the carboxync acid .The reaction mixture is then treated with 100 compound is completed, the amide dissolved in parts of sodium carbonate solutkm and sub 4 therein. Unless otherwise stated, the parts given are by weight.

Example I ..parts of N-octylamine and 6.9 parts of phosthe clear solvent can in most cases be decanted from the gummy precipitate which is metaphosphorous acid. The amide is then crystallized irom the solvent and is thus obtained in excellent purity. It may also be obtained by removing the solvent by steam distillation and subsequently filtering of! the amide or by other suitable means of separation. purification of the amide is necessary or desired, it may be recrystallized in alcohol or some other suitable solvent. In cases where the desired amide is a liquid, after removing any solvent, isolation is generally effected by extracting with ether.

The solvent which is employed for the reaction oi. the phosphazo compound and the carboxylic acid compound may be any normally liquid aliphatic or aromatic hydrocarbon or their chlorinated derivatives such as solvent naphtha, octane, kerosene, benzene, toluene, monochlorbenzene, monochlortoluene. octadecyl chloride, chlorinated kerosene. and the like; oxygenated organic solvents such as ethers and ketones; and normally liquid heterocyclic nitrogenous bases such as pyridine, quinoline, and the like.

It has been indicated above that the phosphazo compounds used in the preparation of the amides of this process have the following general formula:

or the dimer which is represented by the formula:

' (RN=P-NHR) It is, therefore, intended that the general formulae given for the phosphazo compound should be construed as including this cyclic configuration and that the process be not limited to the use of the linear type of compounds for the pro duction of the amides, since the phosphazo compounds, as produced by the reaction of a primary amine with phosphorus trichloride may be formed as the cyclic type of compound. Either form of the phosphazo intermediates will react with the carboxylic acid compounds to form the If any further phorus trichlorid in accordance with the process of our copending application Serial No.

587,211 are heated to reflux temperature and agitated at moderate reflux for some 1-2 hours.

mitted to steam distillation. 13.8 parts (73% of the theoretical) of crude N-octylpropionamide are separated from the aqueous layer. The N- octylpropionamide oil is then dissolved in ether and the ether solution treated with weak hydrochloric acid; the separated N-octylpropionamide is then distilled under reduced pressure and is obtained as a light yellow colored viscous liquid which boils at to 122 C. at 1.5 mm. Analysis: N calculated 7.56, found 7.62.

Example 2 33.4 parts of p-nitrobenzoic acid and 21.4 parts ofphenyl phosphazoanilide are heated in parts of toluene to reflux temperature and maintained at a moderate reflux for 1-2 hours. The reaction mixture is then heated with 200 parts oi 10% sodium carbonate solution and steam distilled to remove toluene and any free aniline which latter may remain from the preparation of the phenyl phosphazoanilide from aniline and phosphorus trichloride. The precipitated product is p-nitrobenzanilide which is filtered from the alkaline solution containing some recoverable unreacted p-nitrobenzoic acid. 42 parts of nitrobenzanilide were obtained having a melting point of 210-211 C. (lit. M. P.=210-211 C).

Example 3 24.4 parts 01 benzoic acid and 180 parts of a,

- toluene solution containing the active phosphorus compound obtained from the reaction of 36.5

- parts of.N-butylamine and 13.8 parts ,of phenphorus trichloride in 80 parts of toluene prepared in accordance with the process of our copending application Serial No. 587,211, are heated to re- 80 flux temperature and agitated at a moderate reflux for from 1-2 hours. The reaction mixture is then treated with 200 cc. of a 10% sodium carbonate solution and subjected to a steam distillation. It is then extracted with ether and the ether evaporated from the extraction mixture. There remain 19.9 parts of N-butyl benzamide which is recrystallized from benzene-petroleum ether to yield 15.9 parts of pure N-butyl-benzamide melting at 41-42 C.

Analysis Calculated Found a as as Example 4 24.4 parts of benzoic acid and 180 parts 01' a toluene solution containing the active phosphorus amides of this application without modification 7 compound obtained from the reaction oi 45.5

of the process. 1

The iollowing examples will further serve to illustrate this invention, it being understood that no limitations are implied and that the invenparts of cyclohexylamine and 18.8 parts of phosphorus trichloride in 80 parts of toluene in accordance with the process of our copending application Serial No. 587,211 are heated to reflux tion is not restricted to the specific materials used :5 temperature and agitated at a moderate reflux for 1-2 hours. After the reaction has been completed, the reaction mixture is allowed to stand until a clear toluene solution separates. It is then decanted and crystallized. 22.7 parts of ben-zamidocyclohexane melted at 145-149 C. (lit. M. P.=149 C.) are obtained. An additional 5 parts of the benzamidocyclohexane may be obtained from the toluene mother liquor by steam distillation from the sodium carbonate solution followed by ether extraction a described in Example 3.

Example 5 24.6 parts of nicotinic acid and 21.4 parts of phenylphosphazoanilide are heated in 170'parts of toluene to reflux temperature and agitated at a. moderate reflux for 1-2 hours. After the reaction has been completed, the hot toluene solution is allowed to separate from a sticky residue which has formed and is then decanted from said sticky residue and chilled by outside cooling. parts of crude nicotinanilide having a melting point of 124-126 C. are thus obtained.

Example 6 86.5 parts of sulfanilic acid and 75 parts of pyridine are heated to reflux temperature and then cooled to 55 C. The mixture is then treated dropwise with a solution of 13.75 parts of phosphorus trichloride in 15 parts of pyridine in accordance with the process of our copending application Serial No. 587,211. The resulting solution is again brought to reflux temperature and agitated at the reflux temperature for 1-2 hours. It is then cooled to 75 C. and 24.4 parts of benzoic acid are added to the mixture which is again heated to reflux temperature. The reaction mixture is maintained at a moderate reflux for 1-2 hours and is then subjected to an alkaline steam distillation. The clear aqueous alkaline solution remaining in the boiler is cooled and the white crystals formed are filtered and dried. 53.6 parts of crude sodium N-benzoylsulfanilate are collected. The crude product is then recrystallized from water.

Analysis Calculated Found Example 7 were obtained having a melting point of 226-227 (lit. M. P.=225) Example 8 16.6 parts of phthalic acid and 21.4 parts of phenylphosphazoanilide (either solid or dissolved.

; tained on recrystallization from ethyl alcohol.

Example 9 8.3 parts of isophthalic acid and 10.4 parts 01' phenylphosphazoanilide (either solid or dissolved in toluene prepared according to our copending application Serial'No. 587,211) are heated in parts of toluene to the reflux temperature and kept at a moderate reflux for 1-2 hours. The reaction mixture is then heated with 100 parts of 10% sodium carbonate solution and steam distilled to remove toluene and any free aniline. The precipitated N ,N-diphenylisophthalamide is filtered oil the alkaline solution containing some isophthalic acid. 13 parts (82% of theoretical) of crude gray amide are thus obtained. The crude materialmay be purified by recrystallization from glacial acetic acid to obtain a product melting at 279-281" C.

This application is a continuation-in-part of our application Serial No. 588,074, filed April 12, 1945, for a Process for the production of organic amides.

Having now disclosed our invention and having set forth the best manner in which to perform it, what we claim as new and desire to protect by Letters Patent is:

The process of producing benzamidocyclohexane which comprises reacting a solution of benzoic acid in toluene with preformed cyclohexyl phosphazo-amino cyclohcxane at the reflux temperature of the toluene and separating the benzamidocyclohexane from the solvent by decanting and crystallization.

HARRY W. GRIMMEL. ALFRED GUENTHER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,146,543 James et al Feb. 7, 1939 2,146,584 Lipkin Feb. 7, 1939 2,186,769 Schirm Jan. 9, 1940 2,302,704 Lincoln et a1 Nov. 24, 1942 2,311,754 Howard et al Feb. 23, 1943 2,384,811 Coleman et a1 Sept. 18, 1945 

